Enantioselective Carbonyl 1,2- or 1,4-Addition Reactions of Nucleophilic Silyl and Diazo Compounds Catalyzed by the Chiral Oxazaborolidinium Ion

Abstract

Conspectus Boron Lewis acid catalysis has a long history and has become one of the most powerful methods for organic synthesis. In addition to achiral boron catalysts such as BX3 (X = F, Cl, Br) and B­(C6F5)3, chiral boron catalysts are also significant synthetic tools used by organic chemists in academic laboratories and industry. Since first reported by Corey et al. in 2002 (J. Am. Chem. Soc.20021243808), the chiral oxazaborolidinium ion (COBI), an activated form of proline-derived oxazaborolidine, has been used as a strong Lewis acid catalyst. Although the early examples of asymmetric synthesis through COBI-catalyzed nucleophilic 1,2- or 1,4-carbonyl additions were reported in 2004–2006, Diels–Alder and cycloaddition reactions of various carbonyl compounds were mostly developed over the next several years to afford enantioenriched cyclized products. The power of COBI in catalyzing carbonyl 1,2- or 1,4-addition reactions triggered our interest in developing asymmetric synthetic methodologies to generate versatile enantiomerically enriched compounds. In this Account, we summarize our recent studies on COBI-catalyzed asymmetric nucleophilic carbonyl addition and tandem reactions. Logical mechanistic explanations of asymmetric COBI catalysis are also discussed. The proton-activated COBI catalyst, which can activate various carbonyl compounds such as aldehydes, ketones, acroleins, and enones through Lewis acid–base interactions and synergistic hydrogen bonds, facilitates asymmetric 1,2- or 1,4-carbonyl additions of nucleophiles. Nucleophiles bearing trialkylsilyl groups successfully reacted with aromatic, aliphatic, and α,β-unsaturated aldehydes through 1,2-addition reactions resulting in chiral β-hydroxy esters. In addition, efficient asymmetric hydrosilylation of ketones was achieved with a TfOH-activated COBI catalyst. Optically active β-keto esters and all-carbon quaternary aldehydes were synthesized successfully through asymmetric 1,2-addition of diazo compounds and tandem H- or C-migration, respectively. In some cases, epoxide products were obtained as side products via the Darzens reaction pathway. Solvent and π–π interactions played important roles in favoring C-migration over H-migration. Nucleophilic 1,4-addition of diazo compounds and chemoselective ring-closure afforded an efficient approach to cyclopropanes, and their tandem rearrangements provided four- and seven-membered cyclic compounds with excellent stereoselectivity. After a Michael addition of diazo compounds, the selective β-hydride shift pathway afforded the β-substituted cyclic enones with high diastereo- and enantioselectivity. The presence of π-bond(s) in the substituents at the α-position of the diazo compound hindered the β-hydride shift pathway and, as a result, favored the cyclopropanation pathway. While there still remain challenges to be overcome, these results further understanding of COBI catalysis and open a window for future development of new asymmetric synthetic methods using carbonyl addition and tandem reactions.

Transient-axial-chirality controlled asymmetric rhodium-carbene C(sp2)-H functionalization for the synthesis of chiral fluorenes

“…etal carbene reaction is one of the most versatile methods for the assembly of valuable molecules with structural complexity and diversity [1][2][3][4][5][6][7][8] . In this regard, the pursuit of practical and efficient catalytic approach has been of long-standing appealing, especially the catalytic asymmetric carbene transformations, such as cyclopropanation 9,10 , X-H insertion 11,12 , C-H insertion [13][14][15][16] , hydride migration 17 , cycloaddition 18,19 , ylide formation followed by rearrangement 20 or interception 21 , and others [22][23][24][25][26][27][28] .…”

Catalytic Asymmetric Darzens‐Type Epoxidation of Diazoesters: Highly Enantioselective Synthesis of Trisubstituted Epoxides

“…After forming tetrahedral intermediate through nucleophilic addition of diazo compounds into aldehyde, H‐migration [12a–d] (Roskamp reaction, path a) and C‐migration (path b) [12e] led to the construction of optically active β‐keto ester and the all‐carbon quaternary aldehyde, respectively (Scheme 1 B). However, epoxide products were observed as side products in the case of o ‐fluorobenzaldehyde [12a] . Based on our observations and reports in the literature, [1a] we envisioned that the reaction of electron‐withdrawing group‐substituted aldehyde such as glyoxal with diazo compound would generate the epoxide through direct ring‐closure of oxygen atom (path c).…”

“…[10] However, no study has been successful in synthesizing trisubstituted epoxides, which remain the most challenging class of oxirane despite having been documented in a Darzens-type aziridination. [6c, 11] Recently, our group reported highly enantioselective catalytic tandem reactions of diazo compounds with the chiral oxazaborolidinium ion (COBI) [12,13] as a Lewis acid catalyst. After forming tetrahedral intermediate through nucleophilic addition of diazo compounds into aldehyde, Hmigration [12a-d] (Roskamp reaction, path a) and C-migration (path b) [12e] led to the construction of optically active b-keto ester and the all-carbon quaternary aldehyde, respectively (Scheme 1 B).…”

Catalytic Asymmetric Darzens‐Type Epoxidation of Diazoesters: Highly Enantioselective Synthesis of Trisubstituted Epoxides

“…Recently, our group reported highly enantioselective catalytic tandem reactions of diazo compounds with the chiral oxazaborolidinium ion (COBI) [12, 13] as a Lewis acid catalyst. After forming tetrahedral intermediate through nucleophilic addition of diazo compounds into aldehyde, H‐migration [12a–d] (Roskamp reaction, path a) and C‐migration (path b) [12e] led to the construction of optically active β‐keto ester and the all‐carbon quaternary aldehyde, respectively (Scheme 1 B). However, epoxide products were observed as side products in the case of o ‐fluorobenzaldehyde [12a] .…”

“…[10] However, no study has been successful in synthesizing trisubstituted epoxides, which remain the most challenging class of oxirane despite having been documented in a Darzens-type aziridination. [6c, 11] Recently, our group reported highly enantioselective catalytic tandem reactions of diazo compounds with the chiral oxazaborolidinium ion (COBI) [12,13] as a Lewis acid catalyst. After forming tetrahedral intermediate through nucleophilic addition of diazo compounds into aldehyde, Hmigration [12a-d] (Roskamp reaction, path a) and C-migration (path b) [12e] led to the construction of optically active b-keto ester and the all-carbon quaternary aldehyde, respectively (Scheme 1 B).…”